chr19-17824811-CA-C

Variant names:

• chr19-17824811-CA-C
• rs147498283
• NM_000215.4:c.*1931delT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000215.4(JAK3):​c.*1931delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00692 in 194,902 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0079 (1 hom.)
• Consequence: JAK3 NM_000215.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.337
• Publications: 0 publications found

Genes affected

JAK3 (HGNC:6193): (Janus kinase 3) The protein encoded by this gene is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations in this gene are associated with autosomal SCID (severe combined immunodeficiency disease). [provided by RefSeq, Jul 2008]

JAK3 Gene-Disease associations (from GenCC):

• T-B+ severe combined immunodeficiency due to JAK3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 19-17824811-CA-C is Benign according to our data. Variant chr19-17824811-CA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 328461.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00664 (1012/152304) while in subpopulation NFE AF = 0.0104 (707/68028). AF 95% confidence interval is 0.00976. There are 6 homozygotes in GnomAd4. There are 442 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.*1931delT		3_prime_UTR_variant	Exon 24 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.*1931delT		3_prime_UTR_variant	Exon 24 of 24		NP_001427368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.*1931delT		3_prime_UTR_variant	Exon 24 of 24	5	NM_000215.4	ENSP00000391676.1
JAK3	ENST00000527031.5	n.2777delT		non_coding_transcript_exon_variant	Exon 14 of 14	2
JAK3	ENST00000696967.1	n.4483delT		non_coding_transcript_exon_variant	Exon 19 of 19
JAK3	ENST00000696968.1	n.*135delT		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 1011 AN: 152186 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00789 AC: 336 AN: 42598 Hom.: 1 Cov.: 0 AF XY: 0.00801 AC XY: 159 AN XY: 19842

African (AFR) AF: 0.00118 AC: 2 AN: 1698

American (AMR) AF: 0.00356 AC: 4 AN: 1124

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 29 AN: 2738

East Asian (EAS) AF: 0.00 AC: 0 AN: 7264

South Asian (SAS) AF: 0.00267 AC: 1 AN: 374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26

Middle Eastern (MID) AF: 0.00763 AC: 2 AN: 262

European-Non Finnish (NFE) AF: 0.0110 AC: 281 AN: 25588

Other (OTH) AF: 0.00482 AC: 17 AN: 3524

GnomAD4 genome AF: 0.00664 AC: 1012 AN: 152304 Hom.: 6 Cov.: 33 AF XY: 0.00593 AC XY: 442 AN XY: 74482

African (AFR) AF: 0.00193 AC: 80 AN: 41550

American (AMR) AF: 0.00660 AC: 101 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0104 AC: 707 AN: 68028

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00300 Hom.: 0

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

JAK3: BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Severe combined immunodeficiency disease Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147498283; hg19: chr19-17935620;